PROJECT SUMMARY/ABSTRACT Mast cell response to stimuli was recently described to be sexually dimorphic with female mast cells exhibiting increased ability to produce and release mediators upon activation. This suggests that female mast cells may have evolutionary advantages and an important role in innate immunity. Our studies indicate that mast cells contribute to host defense against systemic Group B Streptococcus (GBS) infection. The finding of sexual dimorphism of mast cell function is particularly relevant as GBS is associated with pregnancy associated infections apart from its ability to infect nonpregnant adults. The overall goal of this proposal is to test the hypothesis that female mast cells are more efficient than male mast cells in supporting innate immune defense against GBS infections. Our preliminary data indicate that female mast cells produce abundant amounts of coagulation factor XIIIA (FXIIIA) and that FXIIIA deficiency exacerbates GBS systemic infections. Based on these observations, we hypothesize that mast cell-derived FXIIIA plays crucial roles in defense against GBS infections. We will use pregnant and non-pregnant models of GBS infection to test our hypothesis. In Aim 1, we will assess the contribution of FXIIIA and mast cell-derived FXIIIA in preventing GBS dissemination and adverse birth outcomes such as preterm birth. In Aim 2, we will elucidate the mechanisms by which interaction between FXIIIA and GBS surface proteins limit bacterial dissemination and adverse outcomes. In Aim 3, we will determine the underlying mechanisms that contribute to the sexual dimorphism of mast cells, release of FXIIIA and the consequent susceptibility to GBS infections. Together, these studies have the potential to provide novel mechanistic understanding into how mast cells contribute to defense against GBS infection and promotes successful pregnancies. Finally, these studies will lay the groundwork for future projects aimed at exploring the therapeutic potential of mast cell-derived FXIIIA and evaluating sexual dimorphism of other immune cells.